Compositions and methods for treating diseases of the nail

ABSTRACT

Methods and compositions for treating disorders of the nail and nail bed. Such compositions contain a vehicle in which all components of the composition are dissolved, suspended, dispersed, or emulsified, a non-volatile solvent, a wetting agent, and a pharmaceutically active ingredient that is soluble in the non-volatile solvent and/or a mixture of the vehicle and the non-volatile solvent, which composition has a surface tension of 40 dynes/cm or less and has continuing spreadability, and which composition is effective in treating a disorder of the nail or nail bed.

This application claims priority of pending U.S. patent application Ser.No. 12/803,848, filed Jul. 8, 2010.

FIELD OF THE INVENTION

The invention pertains to the field of treatment of diseases of the nailand nail bed. In particular, the invention pertains to methods fortreatment of disorders such as onychomycosis or psoriasis involving thenails.

BACKGROUND OF THE INVENTION

Onychomycosis, a fungal disease of the nail unit caused by yeasts,dermatophytes, or other molds, accounts for approximately 50% of allnail disorders in humans. In about 80% of onychomycosis cases, thetoenails are infected, whereas in the remaining 20%, the fingernails areinfected. The signs and symptoms of this disease include split,thickened, hardened, and rough nail plates, and partial separation ofthe nail plate from the nail bed creating an air gap in some areas.

Another common disorder of nails is nail psoriasis, which affects up to50% of patients with psoriasis. Characteristic nail psoriasis symptomsinclude pitting, which appears as punctuated or irregularly shapeddepressions arranged on the surface of the body of the nail;discoloration of the nail bed; onycholysis or detachment of the body ofthe nail from the nail bed; subungual keratosis; or anomalies of thebody of the nail. Other diseases and disorders involving the nails inhumans and in other animals include onychia, onychocryptosis,onychodystrophy, onychogryposis, onycholysis, onychomadesis,onychophosis, onychoptosis, paronychia, koilonychia, subungual hematoma,and laminitis.

The nail plate is thick, hard, and dense, and represents a formidablebarrier to drug penetration. Although nail material is similar invarious ways to the stratum corneum of the skin, the nail is composedprimarily of hard keratin which is highly disulfide-linked and isapproximately 100-fold thicker than stratum corneum. In certain naildiseases, such as onychomycosis, there is thickening of the nail platewhich further hinders topical drug delivery.

Various topical therapies have been suggested for treatment of naildisorders, such as onychomycosis. Nail lacquers, coating, polishes,enamels, and varnishes have been described. Bohn, U.S. Pat. No.4,957,730, describes a nail varnish containing a water-insolublefilm-forming substance and antimycotic compound. Ferro, U.S. Pat. No.5,120,530, describes an antimycotic nail varnish containing amorolfinein quaternary ammonium acrylic copolymer. The water-insoluble filmformer is a copolymerizate of acrylic acid esters and methacrylic acidesters having a low content of quaternary ammonium groups. Bohn, U.S.Pat. No. 5,264,206, describes a nail lacquer with antimycotic activity,which contains an antimycotic agent and water-insoluble film formersincluding polyvinyl acetate, a copolymer of polyvinyl acetate andacrylic acid, copolymers of vinyl acetate and crotonic acid. Wohlrab,U.S. Pat. No. 5,346,692, describes a nail lacquer for treatingonychomycosis, comprised of a film-forming agent, an antimycoticallyactive substance, and urea, wherewith the antimycotic agent and urea areliberated from the lacquer when the lacquer is applied. A preferredformulation comprises cellulose derivatives as film former, clotrimazoleas the antimycotic agent, dibutyl phthalate as a plasticizer, and amixture of acetone and ethanol as solvent. Nimni, U.S. Pat. No.5,487,776, describes a nail lacquer composition which forms a waterpermeable film containing griseofulvin when the organic solvent systemevaporates, wherein a portion of the griseofulvin is in solution and aportion of griseofulvin is present as a colloidal suspension. Chaudhuri,U.S. Pat. No. 6,143,794, describes a topical formulation for thetreatment of nail fungal infections that includes an antifungal,solvent, gelling agent, adhesion-promoting agent, film-forming agent,surfactant, and optionally a keratolytic agent. The adhesion-promotingagent was a hydroxy-terminated polyurethane such as polyolprepolymer-2.All of these patents and publications describe products applied to thenail that form a substantive nail coating or film containing a drug fromwhich the drug is to penetrate into the nail. None of these methods hasproven to be consistently effective in treating disorders of the nailsuch as onychomycosis.

Various topical therapies utilizing chemical compounds disclosed toenhance penetration through the nail have been described. Knowles, U.S.Pat. No. 5,652,256, describes the use of methyl acetate as a penetrationenhancing compound in combination with naftifine or sulconazole andnaftifine as a topical gel for fungal treatment of the nails. Sorenson,U.S. Pat. No. 5,972,317, discloses that a proteolytic enzyme such aspapain, delivered by pads soaked in the enzyme solution, produces a morepermeable nail. Sun, U.S. Pat. No. 6,231,875, describes acidifiedcompositions of antifungals to enhance transport across nails and skin.Reeves, U.S. Pat. No. 6,391,879, describes the combination of ananti-fungal agent dissolved in an anhydrous blend of polyglycol andDMSO. Although these and other enhanced penetration formulations werereported to increase penetration through the nail, they have not beenshown to be clinically effective in treating conditions of the nail,such as onychomycosis.

Birnbaum, U.S. Pat. No. 7,135,194 discloses a solution to the problem oftopical delivery of medications through the nail plate in a nailafflicted with onychomycosis. Onycholysis and the formation of an airgap between the nail plate and nail bed is common in onychomycosis. Theair gap presents a major barrier to delivering drug to the nailbed.

Birnbaum solves this problem by incorporating an antifungal drug into asolid or semisolid composition, forcing the composition into thesubungual space in the gap between the hyponychium and the nail bed, andpacking this space with the solid or semisolid composition.

Presently, the only topical antifungal product approved by the FDA fortreating onychomycosis is Ciclopirox Nail Lacquer 8% e.g. Penlac®manufactured by Sanofi Aventis, Bridgewater, N.J. The prescribinginformation for Penlac® reports the clinical effectiveness in twoplacebo-controlled studies in onychomycosis patients with target greattoenail involvement of 20 to 65%. Patients applied Penlac® nail lacqueronce daily for 48 weeks and were evaluated for effectiveness at the endof treatment (i.e. 48 weeks or last observation). Complete cure wasdefined as clear nail and negative mycology (absence of the causativefungus by culture and microscopic tests). Almost clear was defined as10% or less nail involvement and negative mycology.

TABLE 1 Study 312 Study 313 Penlac ® Vehicle Penlac ® Vehicle CompleteCure # 6/110 1/109 10/118 0/117 % 5.5 0.9 8.5 0   Almost Clear # 7/1071/108 14/116 1/115 % 6.5 0.9 12   0.9

As shown in Table 1, treatment with Penlac provided a low level ofefficacy. Only 5.5% of treated patients were completely cured and only6.5% of patients were almost cleared of onychomycosis. However, despitethe low effectiveness of topical Ciclopirox Nail Lacquer in treatingonychomycosis, the FDA approved Penlac because of the unmet medical needfor a safe treatment for onychomycosis and the improved safety oftopical applications over systemic anti-fungal agents.

Because of the difficulty in obtaining clinically effectiveconcentrations of medication to the nail bed by topical application of apharmaceutical composition to the affected nail, nail disorders, such asonychomycosis, are typically treated with systemic medications or withtopical medications following removal of the nail. Systemic treatmentfor onychomycosis and other nail disorders is often not satisfactorybecause therapy must be continued for long periods of time, often manyweeks or months, and the medication has effects on tissues other than onthe affected nail. Antifungal compounds, such as miconazole andketoconazole, have been demonstrated to be effective in topicallytreating onychomycosis after nail removal. However, it is clear thatremoval of the nail is a measure than most individuals suffering fromonychomycosis would prefer not to undergo if a less drastic therapeuticmethod would be efficacious.

A select few oral antifungals such as Terbinafine hydrochloride tablets(Lamasil®, Novartis Pharmaceuticals Corporation, East Hanover, N.J.) areapproved in the USA to treat onychomycosis. According to the prescribinginformation for Lamasil® tablets, only 38% of patients achieved acomplete cure, defined as mycological cure plus no nail involvement fortoenail onychomycosis in a 48 week study of Lamasil® treatment for 12weeks and an efficacy evaluation made after a 36 week follow-up periodin order to allow time for involved nail to grow out. Besides the lowlevel of efficacy for Lamasil®, a variety of adverse reactions werereported for Lamasil® in the clinical studies including diarrhea,dyspepsia, abdominal pain, liver test abnormalities, rashes, urticariaand pruritis. The proscribing information for Lamasil® warns of rarecases of liver failure, some leading to death or liver transplant, andisolated reports of serious skin reactions. Additionally, Lamasil®tablets are not recommended for pregnant women or nursing mothers.

Another oral antifungal drug approved to treat onychomycosis of thetoenails is itraconazole, available as 100 mg capsules under theSporanox® brand from PriCare, divisions of Ortho-McNeil-JanssenPharmaceuticals, Inc., Raritan, N.J. The prescribing information forSporanox® capsules reports 14% complete cures (mycological cures plusclear nails) in 214 patients, who were given 200 mg of itraconazoledaily for 12 consecutive weeks. Numerous adverse effects were reportedincluding nausea, vomiting, diarrhea, abdominal pain, edema, fever,fatigue, rash, pruritus, headache, dizziness, hypertension, hypokalemiaand abnormal hepatic function. The prescribing information warns thatSporanox® has been associated with rare cases of serious hepatotoxicity,including liver failure and death. A further warning to prescribers isthat Sporanox® should not be administered for the treatment ofonychomycosis in patients with evidence of ventricular dysfunction suchas congestive heart failure.

Pitre, U.S. Patent Publication 2007/0041910, filed as U.S. patentapplication Ser. No. 11/432,410; and Mallard, U.S. Patent Publication2006/0147383, filed as U.S. patent application Ser. No. 11/315,259,disclose that application of a pharmaceutical composition containing avehicle, a volatile silicone, and a non-volatile oily phase, providesincreased penetration of a pharmaceutically active compound whentopically applied to skin or mucous membrane. This enhanced penetrationis obtained without the use of glycols, such as propylene glycol, whichare known to augment skin penetration of pharmaceutical compounds butwhich are also known to be irritating to skin. The formulations of Pitreand Mallard contain at least 25% w/w of a volatile silicone and, ifformulated with an alcoholic vehicle, contain at least 15% of alcohol.All alcoholic compositions disclosed in Pitre and Mallard containgreater than 50% volatile silicone and the concentration of the volatilesilicone is at least twice the concentration of the alcohol in thecomposition.

Pitre and Mallard do not disclose or suggest the use of suchcompositions for the treatment of diseases of a nail, such asonychomycosis. Moreover, studies have been conducted, including studiesconducted in the laboratories of the present inventors, which show thatthe penetrating ability of an active agent from a composition into skincannot be correlated to the penetrating ability of the active agent fromthe composition into or through a nail.

A significant need remains for a pharmaceutical composition thatprovides for enhanced penetration of a pharmaceutical agent containedwithin the composition into and through a nail and into the nail bed.Such a composition would be valuable for topically treating conditionsaffecting the nail or nail bed, such as onychomycosis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the in vitro penetration of KP-103 throughskin from a formulation of the invention and from three prior artformulations.

FIG. 2 is a graph showing the in vitro penetration of KP-103 throughnail tissue from a formulation of the invention and from three prior artformulations.

FIG. 3 is a graph showing the percentage of nail area affected byonychomycosis from pre-treatment through the follow-up assessment 4weeks post treatment with a formulation of the invention compared to itsvehicle.

DESCRIPTION OF THE INVENTION

It has been unexpectedly discovered that a pharmaceutical compositioncontaining an active pharmaceutical ingredient (API), a solvent,referred to herein as the “vehicle” or the “volatile vehicle”, a wettingagent which may or may not be the same compound as the vehicle, and anon-volatile solvent which has limited water miscibility, having asurface tension of 40 dynes/cm or less, and which composition does notform a solid film when applied to the surface of a nail, providesenhanced penetration of the API through an intact nail and into thenailbed. Preferably, the composition of the invention is free of filmforming polymeric compounds. It is conceived that such compositions maybe used to deliver an API in order to treat medical conditions involvingthe nail and/or the underlying nail bed.

It has been further unexpectedly discovered that one of the mechanismsby which the pharmaceutical composition described herein is effective intreating medical conditions involving the nail or nail bed is due inpart to the low surface tension of the composition. Because thecomposition of the invention has a low surface tension, that is 40dynes/cm or less, when the composition is applied to the surface of thenail, and because the composition when applied to the nail does not forma solid film, not only does the active ingredient penetrate the nail toreach the nail bed, but the composition spreads to wet the nail foldsand is also wicked by capillary action into the gap between the nail andnail bed, without the need to provide pressure or to otherwise force thecomposition into the gap.

Additionally, the preferred lack of film forming polymeric compounds inthe composition contributes to the wickability of the composition intothe gap between the nail and the nail bed as well as the nail folds.

In one embodiment, the invention is a pharmaceutical composition for thetreatment of disorders of the nail or nail bed. The pharmaceuticalcomposition of the invention contains a volatile and/or penetratingvehicle, a non-volatile solvent that is dissolved, suspended, dispersed,or emulsified within the vehicle, an API that is soluble in thenon-volatile solvent and/or a mixture of the vehicle and thenon-volatile solvent and is optionally soluble in the vehicle, and awetting agent, which may or may not be the vehicle itself. The surfacearea of the pharmaceutical composition is preferably 40 dynes/cm orless. In a preferred embodiment, the surface tension of thepharmaceutical composition is 35 dynes/cm or less, more preferably 30dynes/cm or less, and most preferably 25 dynes/cm or less. Preferably,the composition is free of polymeric film forming compounds.

In another embodiment, the invention is a pharmaceutical formulation fordelivery of an API to the nail or nail bed in order to treat disordersof this area. According to this embodiment, the formulation contains avolatile and/or penetrating vehicle, a non-volatile solvent that isdissolved, suspended, dispersed, or emulsified within the vehicle, and awetting agent, which may or may not be the vehicle. The surface tensionof the pharmaceutical formulation is 40 dynes/cm or less, preferably 35dynes/cm or less, more preferably 30 dynes/cm or less, and mostpreferably 25 dynes/cm or less. Preferably, the formulation is free ofpolymeric film forming compounds. The API that is to be used with theformulation of the invention is one that is soluble in the non-volatilesolvent and/or a mixture of the vehicle and the non-volatile solvent andis optionally soluble in the vehicle alone.

In another embodiment, the invention is a method for treating a disorderof the nail or nail bed. According to this embodiment of the invention,a pharmaceutical composition containing a volatile and/or penetratingvehicle, a non-volatile solvent that is dissolved, suspended, dispersed,or emulsified within the vehicle, an API that is soluble in thenon-volatile solvent and/or a mixture of the vehicle and thenon-volatile solvent and is optionally soluble in the vehicle alone, anda wetting agent, which may or may not be the vehicle itself, istopically applied to the surface of a nail that is suffering from adisorder in an amount and for a time sufficient to ameliorate thesymptoms of the disorder. The surface tension of the pharmaceuticalcomposition is 40 dynes/cm or less, preferably 35 dynes/cm or less, morepreferably 30 dynes/cm or less, and most preferably 25 dynes/cm or less.Preferably, the composition is free of polymeric film forming compounds.

As used herein, the term “volatile” when referring to the vehicle meansthat the vehicle is a compound that evaporates from the surface of thenail when applied. Volatile vehicles are compounds which have ameasurable vapor pressure, and preferably are compounds that have avapor pressure of greater than about 100 Pa at room temperature.Examples of volatile vehicles include: acetone,2-amino-2-methyl-1-propanol, 1,2-butanediol, 1,4-butanediol, 2-butanol,cyclomethicone-4, cyclomethicone-5, cyclomethicone-6, ethanol, ethylacetate, n-heptane, isobutanol, isopropyl alcohol, 1-propanol,2-propanol, and water.

As used herein, the term “penetrating” when referring to the vehiclemeans that the vehicle is a compound that rapidly penetrates into a nailwhen applied to the surface of the nail so that, after 10 minutesfollowing the application of a thin layer of the vehicle onto thesurface of a nail, no more than 10% of the applied amount remains on thenail surface. The term Apenetrating@ thus includes both volatile andnon-volatile vehicles.

As used herein, the term “surface tension” refers to the force requiredto increase unit area of a surface of a liquid or of an interfacebetween two liquids or between a liquid and a gas, generally stated inunits of dynes/cm. Surface tensions described herein are measured by theDu Noüy ring method utilizing an EasyDyne tensiometer model K20 marketedby Krüss USA, Matthews, N.C.

Examples of pharmaceutical compositions that may be used in the methodof the present invention, provided such compositions have a surfacetension of 40 dynes/cm or less, are disclosed in Pitre, U.S. patentapplication Ser. No. 11/432,410; and in Mallard, U.S. patent applicationSer. No. 11/315,259, which applications are incorporated herein in theirentirety. In accordance with the present invention, the pharmaceuticalcompositions of Pitre and Mallard that may be used to treat medicalconditions of the nail in accordance with the present invention maycontain Vitamin D as the API as disclosed in Pitre or clobetasol asdisclosed in Mallard, or may contain other APIs in place of, or inaddition to, these APIs, as disclosed herein.

The API of the composition of the invention is one that is useful in thetreatment of a disorder of the nail or nail bed. The API is soluble inthe solvent of the composition and/or in the combination of the solventand vehicle of the composition. Examples of suitable APIs includeanti-inflammatory agents, antimicrobial agents such as antibiotics andantifungal agents, anesthetic agents, steroidal agents, vitamins andderivatives thereof, anti-psoriatic drugs, and analgesic agents.

In a preferred embodiment, the API of the composition of the inventionis an antifungal chemical compound, particularly those effective in thetreatment of onychomycosis. Examples of suitable antifungal agentsinclude polyene antimycotic agents such as natamycin, rimocidin,filipin, nystatin, and amphotericin B; imidazole compounds such asmiconazole, ketoconazole, clotrimazole, econazole, bifonazole,butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole,suconazole, and tioconazole; triazole compounds such as fluconazole,itraconazole, ravuconazole, posaconazole, voriconazole,(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol(referred to herein as “KP-103”), and terconazole; allylamine compoundssuch as terbinafine, amorolfine, naftifine, and butenafine; echinocandincompounds such as anidulafungin, caspfungin, and micafungin; and otherantifungal drugs such as ciclopirox, flucytosine, griseofulvin, gentianviolet, haloprogin, tolnaftate, and undecylenic acid. Any antifungalcompound suitable for pharmaceutical use in humans or mammals, andparticularly those which are active in vitro against Candida albicans,Trichophyton rubrum or Trichophyton mentagrophytes, is suitable for theAPI of the invention. Particularly preferred are antifungal APIs thathave relatively low binding to keratin, such as triazole compounds likeKP-103.

Other APIs that are suitable for the composition of the inventioninclude those that are effective in treating diseases and disorders ofnails other than onychomycosis, especially those diseases and disordersaffecting tissues deep to the external surface of the nail, such as theinternal portion of the nail, the deep nail surface adjacent to the nailbed, and the nail bed. Such diseases and disorders may include onychia,onychocryptosis, onychodystrophy, onychogryposis, onycholysis,onychomadesis, onychophosis, onychoptosis, paronychia, koilonychia,subungual hematoma, and laminitis. Drugs other than antifungal agentsthat are suitable for the composition of the invention includecorticosteroids such as clobetasol propionate, betamethasonedipropionate, halobetasol propionate, fluocinonide and mometasonefuroate, keratolytic agents such as urea and salicylic acid, orantibacterials/antibiotics such benzoyl peroxide, mupirocin,erythromycin, bacitracin, chlorotetracyciline and cetylpyridiniumchloride.

The vehicle of the composition of the invention is a pharmaceuticallyacceptable vehicle in which the constituents of the composition of theinvention can be dissolved, suspended, disbursed, or emulsified. Theconstituents of the composition may be all within a single phase in thevehicle. For example, the API, wetting agent, and the non-volatile phasemay be dissolved in the vehicle. Alternatively, the constituents mayoccupy separate phases within the vehicle. For example, the API may bedissolved in the vehicle and the other constituents may be suspended,dispersed, or emulsified in solvent. For another example, the API may bedissolved in the solvent which is suspended, dispersed, or emulsified inthe vehicles, with the remaining constituents being dissolved in eitherthe vehicle or the solvent. Preferably, but not necessarily, the API,wetting agent, and non-volatile phase are all miscible in the vehicle.

Examples of suitable vehicles include one or more of water, alcohols,polyols, ethers, esters, aldehydes, ketones, fatty acids, fattyalcohols, and fatty esters. Specific examples of suitable vehiclesinclude ethanol; 3-propanediol; 1,2-butanediol; 1,2,3-propanetriol;1,3-butanediol; 1,4-butanediol; isopropyl alcohol; and2-amino-2-methyl-1-propanol. In a preferred embodiment, the vehicle isan alcohol, and most preferably a linear or branched aliphatic loweralcohol, such as methanol, ethanol, propanol, or isopropanol.

The wetting agent of the composition of the invention is a chemicalcompound that reduces the surface tension of liquid compositions anddoes not build viscosity. Any surfactant or group of surfactants that issuitable for dermatologic applications is suitable for the invention.Such surfactants may function as wetting agents in the compositions ofthe invention, and as emulsifiers or solubilizers. The surfactants maybe nonionic, anionic, cationic, zwitterionic, amphoteric, or ampholyticsurfactants.

Examples of non-ionic surfactants include polyoxyethylene sorbitan fattyacid esters such as polysorbate 20, 40, 60 and 80; sorbitan esters suchas sorbitan monolaurate, sorbitan monooleate, sorbitan monostearate, andsorbitan trioleate; polyoxyethylene alkyl ethers such as Brij 30, Brij97, Emulgen 104P, 210P, 200 and Ethylan 253, 254, 256, and 257,polyoxyethylene castor oil derivatives such as polyoxyl 35 castor oil.

Examples of cationic surfactants include fatty amines; quaternaryammonium compounds; as well as cationic copolymers, cationic mixedpolymers, cationic polysaccharides, cationic cellulose derivatives,cationic or cationized hydrolyzed proteins such as collagen or keratin,or a mixture thereof. Specific examples of cationic surfactants includecetyltrimethylammonium chloride, behenyltrimethylammonium chloride,cetylpyridinium chloride, tetramethylammonium chloride,tetraethylammonium chloride, octyltrimethylammonium chloride,dodecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride,octyldimethylbenzylammonium chloride, decyldimethylbenzylammoniumchloride, stearyldimethylbenzylammonium chloride,didodecyldimethylammonium chloride, dioctadecyldimethylammoniumchloride, tallow trimethylammonium chloride, cocotrimethylammoniumchloride, and the corresponding hydroxides thereof; quaternary esters,such as tetradecylbetaine ester chloride; diquaternary esters, such asdipahnitoylethyldimethylammonium chloride; and diquaternary silicones.

Examples of anionic surfactants include but are not limited to thosebased on sulfate, sulfonate, or carboxylate anions. Examples of suchanionic surfactants include sodium laureth sulfate, alkyl benzenesulfonates, soaps, fatty acid salts, and alkyl sulfate salts such assodium lauryl sulfate, also known as sodium dodecyl sulfate, andammonium lauryl sulfate.

Examples of amphoteric (zwitterionic) surfactants include but are notlimited to dodecyl betaine, dodecyl dimethylamine oxide, cocamidopropylbetaine, and cocoamphoglycinate.

Preferably, the wetting agent is a volatile silicone. Such volatilesilicones include linear or cyclic polyorganosiloxane compounds offormula [R₁SiOR₂]_(n) wherein n=6 or less and R₁ and R₂ are alkyl groupsthat may be the same or different, and which compound has a measurablevapor pressure under ambient conditions. Preferably, n=from 3 to 6, andmost preferably n=4 or 5. Preferably R₁ and R₂=methyl.

Examples of cyclic volatile silicones includepolydimethylcyclosiloxanes, generally known as cyclomethicones.Particular examples of cyclic volatile silicones includecyclopentasiloxane, cyclotetrasiloxane, decylmethylcyclopentasiloxane,and octylmethylcyclotetrasiloxane. Examples of linear volatile siliconesinclude linear polysiloxanes. Particular examples of linear volatilesilicones include hexamethyldisiloxane, octamethyltrisiloxane, anddimethicones.

In one particular embodiment of the invention, a single compound formsboth the vehicle and the wetting agent of the composition. For example,the vehicle may be a volatile silicone. In this situation, the volatilesilicone may also be the wetting agent of the composition. In the casein which the wetting agent serves also as the vehicle, the concentrationof the wetting agent in the composition is sufficiently high to functionas a vehicle in which all other components of the composition aredissolved, suspended, dispersed, or emulsified.

The non-volatile solvent of the composition is a non-aqueous solventthat may or may not be soluble or miscible in the vehicle of thecomposition. The API of the composition is preferably, but notnecessarily, soluble in the non-volatile solvent. In a preferredembodiment wherein the API is hydrophilic, the non-volatile solvent is apolar or semi-polar molecule. In another preferred embodiment whereinthe API is hydrophobic, the non-volatile solvent is non-polar.

Suitable non-volatile solvents for hydrophobic drugs are disclosed inPitre, U.S. patent application Ser. No. 11/432,410 in paragraphs 0069 to0082, which paragraphs are incorporated herein by reference. Forexample, the non-volatile solvent may be an ester of the formulaRCO—OR′, wherein R and R′ may be identical or different and each of Rand R′ represents a linear or branched chain of an alkyl, alkenyl,alkoxycarbonylalkyl, or alkoxycarbonyloxyalkyl radical having from 1 to25 carbon atoms, preferably from 4 to 20 carbon atoms. The non-volatilesolvent may be a glyceryl ester of a fatty acid, such as fatty esters ofnatural fatty acids or triglycerides of animal or plant origin. Thenon-volatile solvent may be a fatty acid glyceride, including syntheticor semi-synthetic glyceryl esters, such as fatty acid mono-, di-, ortriglycerides, which are oils or fats. The non-volatile solvent may be anon-volatile hydrocarbon, such as paraffins, isoparaffins, and mineraloil. The non-volatile solvent may be a guerbet ester. The non-volatilesolvent may be a non-volatile silicone, provided that the presence ofthe non-volatile silicone in the composition does not result in theformation of a hard polymeric film upon application of the compositiononto a nail. Included within such non-film forming silicones arepolyorganosiloxane compounds that have the formula [R₁SiOR₂]_(n) whereinn>6 and R₁ and R₂ are alkyl groups that may be the same or different,and which compound may or may not have a measurable vapor pressure underambient conditions.

Other examples of suitable non-volatile solvents for hydrophobic drugsin addition to those disclosed in Pitre include squalane, dibutylsebacate, isopropyl laurate, isopropyl myristate, isopropyl palmitate,isopropyl strearate, myristyl alcohol, oleyl alcohol, oleic acid, lauryllactate, myristyl lactate, mixed C12-15 alkyl lactates, diisopropyladipate, octyldodecanol, caproic acid, caprylic acid, capric acid,lauryl benzoate, myristyl benzoate, mixed C12 15 alkyl benzoates, benzylbenzoate, tridecyl neopentanoate, light mineral oil, mineral oil, andalpha terpineol. Examples of suitable non-volatile solvents forhydrophilic drugs include diethylene glycol monoethyl ether,n-methylpyrrolidone, dimethyl sulfoxide, ethyl lactate, hexylene glycol,glycerol, benzyl alcohol and glycerol triacetate.

The composition of the invention may contain additional optionalcomponents, such as preservatives, stabilizers, lubricants, humectants,moisture regulators, foaming agents, binders, pH regulators, osmoticpressure modifiers, emulsifiers, antioxidants, colors, aerosolpropellants, fragrances, or odor maskers. If desired, the compositionmay also contain additional nail modifiers or penetration enhancers,such as urea, propylene glycol, sodium lauryl sulfate, and glycolicacid.

The composition is intended to remain in a liquid or semi-solid stateafter application to the nail and does not form a hard lacquer, shell,or film on the nail following application, which occurs by a process ofsolvent casting following evaporation of a volatile solvent which leavesbehind a solid residue that forms the lacquer, shell or film which islasting, hard, and/or adherent. Therefore, it is preferred that thecomponents of the composition are miscible in the composition and alsoare miscible in the “secondary” composition that remains after thevolatile vehicle has evaporated or penetrated the nail. It is alsosuitable for the components of the composition, other than the vehicle,to be suspendible, dispersible, or emulsifiable, in the secondarycomposition, such as in the non-volatile solvent.

The composition has a surface tension that is sufficiently low so that,when the composition is applied to the surface of a toenail on a humansubject, the composition spreads into the nail folds and also is wickedinto the gap between the nail and the nail bed if such a gap is present.A gap is generally present in a nail that is suffering from a disordersuch as onychomycosis. Preferably, the surface tension of thecomposition is 40 dynes/cm or less, more preferably 35 dynes/cm or less,even more preferably 30 dynes/cm or less, and most preferably, thesurface tension is 25 dynes/cm or less.

It is preferred that the composition, when applied to the surface of anail, does not form a solid film or lacquer and it is most preferredthat the composition is free of polymeric film forming compounds.Examples of polymeric film forming compounds include polymers andcopolymers of polyvinyl acetate, polyvinylpyrrolidone, methacrylic acid,polyvinyl butyrals, polyvinyl acetals, and cellulose derivatives such ascellulose acetate phthalate, cellulose acetate butyrate, celluloseacetate propionate, cellulose nitrate, cellulose sulfate,ethylcellulose, and cellulose acetate. A polymeric film forming agentmay be present in the composition of this application if it is presentin an amount below that which will result in the formation of a film orlacquer following application of the composition to the surface of anail.

The spreadability of a composition may be defined by a test such as thesingle slide spreadability test, which may be performed as follows. Onehundred microliters of a test formulation is applied to a single pointon the surface of a clean dry single glass slide. The area of spread ofthe formulation on the glass slide is determined at various timesfollowing the application, such as at 1, 2, 4, 6, and 10 minutes.Formulations that are most suitable for the present method continue tospread on the surface of the slide throughout the first 6 minutes andpreferably throughout the first 10 minutes. Preferably, but notnecessarily, the area of coverage of the formulation on the slide after10 minutes is higher than 11.0 cm².

The composition of the invention may be prepared in any number of forms,such as creams, milks, salves, impregnated pads, solutions, tinctures,liniments, liquids, sprays, foams, suspensions, gels, or lotions. Thecomposition may be formulated to provide for immediate or controlledrelease of the API from the composition.

The concentration of the various essential and optional components ofthe composition of the invention will vary, depending on the particularcomponents contained in the composition, the form of the composition,the particular disease or condition that is to be treated with thecomposition, and whether the formulation is for immediate or forcontrolled release.

The API of the composition is at a concentration that is effective totreat a disorder or disease of the nail or nail bed. Typically, theconcentration of the API will constitute between 0.0001 to 30% or higherby weight of the composition.

The concentration of the wetting agent in the composition may varydepending on several factors, including the identity of the wettingagent and whether the wetting agent is also the vehicle of thecomposition. Generally, the concentration of the wetting agent, such asa volatile silicone, will be between 0.001% and 95% by weight of thecomposition. Preferably, the concentration of the wetting agent isbetween 0.01% and 80%, more preferably between 0.1% and 60%, and mostpreferably between 1% and 40% w/w of the composition. In a particularlypreferred embodiment, the concentration of wetting agent in thecomposition is between 2% and 15% w/w. In the case where the wettingagent is not functioning as a vehicle of the composition, theconcentration of wetting agent in the composition will generally betowards the lower end of the above range of concentration, such asbetween 0.001% and 10%.

The concentration of the non-volatile solvent will constitute between 0%and 90% w/w of the composition. Generally, with less viscous forms ofthe compositions, lower concentrations of non-volatile phase will bepresent, and with more viscous forms, higher concentrations of thenon-volatile phase will be used. Also, predominately oil-basedcompositions tend to have a higher concentration of non-volatile phaseor components than do compositions such as sprays, gels, and lotions andso will have a higher concentration of a non-volatile solvent. Typicalconcentrations of non-volatile solvent are between 10 and 80%, withpreferred concentrations being between 12 and 60%, and most preferredconcentrations between 15 and 50% w/w.

The concentration of the vehicle will be that which is sufficient todissolve, suspend, disperse, or emulsify the other components of thecomposition. In many but not all cases, the concentration of the vehiclewill be higher than that of any other constituent of the composition. Insome cases, the concentration of the vehicle will be higher than that ofthe combined concentration of the other constituents of the composition.In a preferred embodiment in which the vehicle is an alcohol, thecomposition will contain at least 10% alcohol, more typically at least15% alcohol, and most typically at least 25% alcohol. The concentrationof alcohol in the composition may be as high as 80%, or higher. In onepreferred embodiment, the concentration of alcohol is at least 50% w/wof the composition.

In a particularly preferred embodiment of the invention, the compositionof the invention is an alcoholic composition containing a volatilesilicone. In a first preferred embodiment, the ratio of alcohol tovolatile silicone in the composition % w/w is at least 2:3, preferablyat least 1:1, more preferably at least 2:1, and most preferably at least3:1. In a second preferred embodiment, the concentration of the volatilesilicone in the composition is less than 25% w/w. In a third preferredembodiment, the concentration of the alcohol in the composition is atleast 40%, more preferably at least 45%, and most preferably at least50% w/w. The composition of the invention, according to this embodimentof the invention, may be made so as to encompass any one, two, or allthree of the embodiments described above. It has been determined that,when applied to the surface of a nail, the alcoholic composition of theinvention containing a volatile silicone provides a high degree ofpenetration of an API contained therein into the nail.

Although the compositions of the invention may be used to treat variousdiseases and disorders of the skin or mucous membranes, they are mostadvantageously used to treat conditions involving the nails of the handsor feet. The compositions and methods of the invention provide increasedpenetration of API in the composition into and through the nail and tothe nail bed. The compositions of the invention may be used effectivelyto treat diseases and disorders in humans or in other animals, such ascats, dogs, horses, cattle, sheep, goats, pigs, and birds. In human andin veterinary patients, the compositions of the invention may be used,depending on the particular animal treated, to treat conditionsinvolving nails, hooves, horns, or beaks.

The compositions of the invention are especially well suited for thetreatment of onychomycosis and other disorders of the nail and nail bed.The composition is topically applied to the surface of the nail andsurrounding tissue by any means by which the composition may be applied.The method of application may vary depending on the physical state ofthe composition, whether it is in a liquid, semisolid, or solid form,and on the viscosity of the composition if it is a liquid. Thus, forexample, the composition may be rubbed, painted, dabbed, dripped,sprayed, wiped, spread, or poured onto the affected nail and surroundingtissues, or utilized as a soak. Frequency of treatment and duration oftherapy will very depending on several factors, including the conditionthat is being treated, the identity and concentration of the API in thecomposition, and constituents of the composition other than the API.Typically, the frequency of treatment will be twice daily to onceweekly, and preferably once daily. The preferred duration of topicaltreatment is at least 36 weeks and preferably longer, such as 40 weeksor 48 weeks. The preferred criterion for treatment efficacy is completecure, which can be assessed at the end of treatment, but is preferablyassessed 4 to 12 weeks after the end of treatment, most preferably 4weeks after the end of treatment.

To further illustrate the invention, the following examples areprovided. It is to be understood that these examples are provided forillustrative purposes and are not to be construed as limiting the scopeof the invention. It is to be further understood that, in the examplesthe functions of individual ingredients are sometimes listed forillustration purposes. However, it is understood that not all functionsof the ingredients are listed and that many excipients have multiplefunctions.

Example 1 Skin Penetration Study

Four different formulations were tested to determine the penetrabilityof an API into skin. The formulations each contained 5.00% w/w of atriazole antifungal API compound, KP-103. The compositions of the fourformulations are shown in Table 2. All concentrations of the componentsof the formulations are in % w/w.

TABLE 2 Formulation No. 078 080 082 107 KP-103 5.00 5.00 5.00 5.00alcohol 19.35 20.00 59.998 — triacetin 15.00 — — — glycerin 35.00 24.998— — 1,3-butylene glycol 25.00 — — — carbomer 980 0.50 — — —diisopropanolamine 0.10 — — — Vitamin E 0.05 0.002 0.002 0.05 propyleneglycol — 50.00 — — cyclomethicone — — 13.00 — diisopropyl adipate — —12.00 8.20 myristyl lactate — — 10.00 — isopropyl myristate — — — 5.48white petrolatum — — — 51.27  urea — — — 30.00 

Each of the formulations of Table 2 was spiked with tracer amounts ofradiolabeled KP-103 at approximately 0.90 μCi/dose. A single clinicallyrelevant dose (5 mg/cm2) was applied to dermatomed human skin obtainedfrom one donor following elective surgery.

Percutaneous absorption was evaluated by mounting the dermatomed tissuein Bronaugh flow-through diffusion cells at 32 C. Six replicates wereperformed for each formulation. Fresh receptor fluid, PBS containing0.1% w/v sodium azide and 1.5% Oleth-20, was continuously pumped underthe skin at a nominal flow rate of 1 ml/hr and collected in 6-hourintervals. Following 24-hours of exposure, the residual formulationremaining on the skin surface was removed by repeated tape stripping (5strips/cell). Subsequently, the epidermis was physically separated fromthe dermis by gentle peeling. The quantity of radioactivity in thetape-strips, epidermis, dermis, and receptor fluid samples wasdetermined using liquid scintillation counting. The results for thecalculated quantity of API collected in the receptor for each of theformulations of Table 2 are shown in FIG. 1.

As shown in FIG. 1, Formulations 080 and 107 demonstrated considerablyhigher skin penetration than did Formulations 078 and 082. Formulation080 contains propylene glycol, a known skin-penetration enhancer, andexhibited a higher penetration through skin than any of the otherformulations. Formulation 107 contains urea, a known skin-penetrationenhancer, and exhibited the second highest skin penetration of the fourformulations tested. Formulation 082 is a formulation according to thepresent invention and exhibited the lowest skin penetration of thetested formulations. Formulation 078 is a composition that is not withinthe scope of the invention and exhibited slightly higher penetrationinto and through skin than did Formulation 082. Of the fourformulations, the formulation with the lowest level of skin penetrationwas formulation 082, the only formulation of the four that is acomposition of the invention.

Example 2 Nail Penetration Study

The formulations 078, 080, 082, and 107 of Example 1 were tested todetermine penetration of the API from the formulation into and throughnail plates. Each of the formulations of Table 2 was spiked with traceramounts of radiolabeled KP-103 at approximately 0.90 μCi/dose. Aclinically relevant protocol was followed, which entailed dosing 10μL/cm² per day for 14 days onto healthy human finger nail plates, whichwere obtained from multiple donors.

Nail penetration was evaluated by mounting the finger nail plates intocustom diffusion cells. Five replicates were performed for eachformulation. A small cotton ball wetted with 0.1 mL normal saline wasused as a receptor. For each day of the study, the surface of the nailwas washed, and 10 μL of formulation was applied to the surface. Everysecond day, the cotton ball receptor was replaced. After fourteen daysof exposure, the nail plate was sectioned into three sections, a centraldorsal (upper) section, central ventral (lower) section and theremaining peripheral material. The quantity of radioactivity in thedaily surface washes, cotton ball receptors, dorsal nail, ventral nailand peripheral nail was determined using liquid scintillation counting.

The results are shown in FIG. 2. As shown in FIG. 2, the formulation ofthe invention, Formulation 082, provided over 6 times the penetrationthrough the nail and into the saturated cotton ball receptor than didthe other formulations, calculated as a percentage of the applied dose.The penetration of Formulations 080 and 107 had been expected to behighest through nail because they had exhibited a significantly higherpenetration through skin. However, the penetration of API fromFormulations 080 and 107 was, in fact, lower than from the otherformulations even though these Formulations 080 and 107 contained wellknown skin penetration enhancers. This study establishes that thepenetration of API from a formulation through skin is not predictive ofthe penetration of the API from the formulation through nail tissue.This study further establishes the unexpected ability of a preferredformulation of the invention, Formulation 082, to increase thepenetration of API within the formulation through nail tissue.

Example 3 Clinical Assessment in Animal Model of Onychomycosis

The efficacy of a formulation of the invention, Formulation 087,containing 3.00% w/w of a triazole antifungal API, KP-103, was evaluatedin an animal model of onychomycosis and, in two separate studies, wascompared with that of several commercial products intended for thetreatment of onychomycosis. The composition of Formulation 087 is shownin Table 3.

TABLE 3 FORMULATION 087 Component Concentration (% w/w) KP-103 3.00Alcohol 60.00 Vitamin E 0.002 Cyclomethicone 13.00 Diisopropyl adipate10.00 Myristyl lactate 13.998

In order to test the efficacy of Formulation 087 and the comparisonproducts, onychomycosis was induced in six-week old Hartley guinea pigs.Each of Formulation 087 and the comparison products were tested in fiveanimals. Two hundred (200) μL of a suspension of Trichophytonmentagrophytes SM-110 (1×10⁸ arthrospores/mL) was inoculated to theplantar and interdigital skin of the hind paws, and the entire feet werethen covered with bandage. The bandage was removed 28 days after fungalinoculation. Test treatments were applied for a period of 30 days,starting on the 60th day after infection.

The infected nails were removed from the feet 7 days following the finaltreatment and were minced with scissors. The nails were placed in aglass homogenizer and PBS (phosphate buffer solution) containing 0.25%porcine pancreatic trypsin was added at a rate of 1 mL/50 mg of wet nailweight, and the nail was homogenized. The homogenate was allowed tostand at 37° C. for 1 hour. One hundred microliters of the nailhomogenate or its dilution was spread on a GPLP agar medium containingantibiotics and cultured at 30° C. for 7 days. After culturing, thefungal colonies that appeared on the medium were counted, and the numberof colony forming units (CFU) of fungi in the nails was calculated. Thenail sample was considered culture-negative when no fungal colonyappeared on the plate.

In Study 1, the efficacy of Formulation 087, applied to the nails at 30μL/foot once a day for 30 days, was compared with untreated controlanimals and with 5% Amorolfine lacquer (Loceryl®) applied to the nailsat 30 μL/foot once a week for 30 days. In Study 2, 1% naftifine gel(Naftin®) and 8% ciclopirox lacquer (Penlac®), each applied to the nailsat 30 μL/foot once a day for 30 days, were compared with untreatedcontrol animals. The results of Study 1 and Study 2 are shown in Table4.

TABLE 4 No. of feet with Mean no. of CFU in culture-negative nails/nails/foot after total no. of feet Treatment treatment (Log 10) (%)after treatment Study 1 Control (no treatment) 29512 (4.47 +/− 0.37) N/A5% Amorolfine lacquer  2398 (3.38 +/− 0.87) 0/10 (0%)  (Loceryl⁷)Formulation 087   63 (1.80 +/− 0.53) 6/10 (60%) Study 2 Control (notreatment) 10964 (4.04 +/− 0.69) N/A 1% Ciclopirox lacquer  214 (2.33+/− 1.10) 1/10 (10%) (Penlac⁷) 1% Naftifine gel  501 (2.70 +/− 1.45)1/10 (10%) (Naftin⁷)

The data of Table 4 establishes that the formulation of the inventionwas more efficacious in treating onychomycosis in an animal model ofhuman disease than were several currently available therapies foronychomycosis. With Formulation 087 of the invention, 60% of theinfected nails were culture-negative following treatment. With thecompositions of the prior art, 10% or less of the infected nails wereculture-negative following treatment.

Example 4 Clinical Assessment in Human Treatment

An adult male human suffering from onychomycosis of the left largetoenail was treated daily by topical application of a 10% topicalformulation of the invention containing KP-103. Additional components ofthe 10% topical formulation were alcohol, vitamin E, butylatedhydroxytoluene, cyclomethicone, diisopropyl adipate, and C12-15 alkyllactates. Nail involvement at the initiation of treatment was 80% withonycholysis (separation of the nail plate from the nail bed) andthickening of subungual area. Following six months of treatment, thediseased proximal portion of the nail had grown out beyond the distalend of the nail plate (hyponychium) and was subsequently clipped off.There was no active fungal involvement of the nail plate, signs ofonycholysis or thickening of the subungual area, or nail involvementafter 6 months of treatment.

Example 5 Additional Formulations of the Invention Containing KP-103

Several additional formulations of the invention were made containingidentical components, but in varying concentrations (% w/w), as shown inTable 5.

TABLE 5 Formula- Formula- Formula- tion A 10% tion B 5% tion C MATERIALFUNCTION SOLUTION SOLUTION VEHICLE Alcohol vehicle 56.73 59.85 63.04Cyclomethicone wetting 12.30 13.00 13.67 agent Diisopropyl non-volatile11.36 12.00 12.62 adipate solvent C12-15 alkyl non-volatile 9.46 10.0010.52 lactate solvent KP-103 API 10.00 5.00 0.00 Vitamin E anti-oxidant0.05 0.05 0.05 Butylated anti-oxidant 0.10 0.10 0.10 hydroxytoluene

Example 6 Determination of Surface Tension

The surface tension of Formulation 087 shown above in Table 3 in Example3 and the surface tension of the Formulations A, B, and C of Example 5were determined at ambient room temperature of 21° to 25° utilizingabout 30 grams of each solution on a Krüss Surface Tensiometer, ModelK20 Easy Dyne (Krüss USA, Matthews, N.C.). The surface tension value foreach of the formulations is shown below in Table 6.

TABLE 6 Formulation Formula- Formula- Formula- Formula- tion 087 tion Ation B tion C Surface Tension 22.1 22.1 22.0 21.8 (dynes/cm)

Example 7 Additional Formulations and Vehicles

Additional formulations in accordance with the present description,either containing or lacking an active pharmaceutical ingredient, weremade as shown in Table 7.

TABLE 7 Formu- Formu- Formu- Formu- lation lation lation lation D (% E(% F (% G (% MATERIAL FUNCTION w/w) w/w) w/w) w/w) Glycerin vehicle18.405 Ethyl Alcohol vehicle 63.04 20.00 19.85 Isopropyl Alcohol vehicle54.85 Cyclomethicone wetting agent 6.835 13.00 13.00 13.00 Diisopropylnon-volatile 6.31 12.00 12.00 12.00 adipate solvent C12-15 alkylnon-volatile 5.26 10.00 10.00 10.00 lactate solvent Benzyl Alcoholvehicle 34.85 N-methyl-2- non-volatile 35.00 pyrrolidone solvent KP-103API 0.00 10.00 10.00 10.00 Vitamin E anti-oxidant 0.05 0.05 0.05 0.05Butylated anti-oxidant 0.10 0.10 0.10 0.10 hydroxytoluene

In contrast to Formulations A-C of Example 5 in which the vehicle isethyl alcohol, the vehicle of Formulation D is a combination of ethylalcohol and glycerin, a water-miscible polyol. Formulations E and Fcontain a low concentration of ethyl alcohol compared to FormulationsA-D. In Formulation E, the vehicle is a combination of ethyl alcohol andbenzyl alcohol. In Formulation F, the vehicle is ethyl alcohol. InFormulation G, the ethyl alcohol has been replaced with isopropylalcohol.

Example 8 Determination of Surface Tension of Formulations of Example 7

The surface tensions of Formulations D to G of Example 7 were determinedby the method described in Example 6. The surface tension value for eachof the formulations is shown below in Table 8.

TABLE 8 Formulation Formula- Formula- Formula- Formula- tion D tion Etion F tion G Surface Tension 22.4 21.6 21.7 21.7 (dynes/cm)

Example 9 Determination of Spreadability

The spreadability of each of Formulations 087 and A to G of Examples 3,5, and 7 was determined at ambient room temperature of 21° to 25° byutilizing a single glass slide that had been cleaned with isopropylalcohol and permitted to air dry. 100 microliters of a formulation wasplaced onto a single point on the cleaned glass slide by positivedisplacement pipette. The glass slide was placed on graph paper with 0.5cm×0.5 cm grids to facilitate diameter determinations. The area coveredby each of the formulations was essentially circular. The diameter ofthe spread of the drop was recorded at 1, 2, 4, 6, and 10 minutes. Areawas calculated using the following equation. Data is shown in Table 9.Covered area (cm²)=π(d/2)² =πr ²

-   -   π=3.141592654    -   d=diameter (cm)    -   r=radius (cm)

TABLE 9 Min- Formulations utes 087 A B C D E F G Single 1 4.9 4.9 5.97.1 4.0 4.9 4.9 5.9 Slide 2 7.1 7.1 9.6 10.2 5.9 7.1 7.1 7.1 Spread- 49.6 9.6 15.9 15.9 14.9 12.6 12.6 8.3 ability 6 15.9 15.9 23.8 23.8 21.617.7 14.2 9.6 Area 10 28.3 28.3 33.2 33.2 28.3 33.2 14.9 19.6 (cm²)

Each of the tested formulations exhibited a single slide spreadabilitythat continued to increase during the 10 minutes of the test. Further,each of the tested formulations had a spreadability area of at least14.0 cm² within 10 minutes.

Example 10 Additional Formulations (Prior Art)

Additional formulations H and I, not in accordance with the presentdescription, were made as shown in Table 10. Formulation H is 100% waterand Formulation I is a combination of 63% ethyl alcohol and 37%octocrylene. An additional formulation was Formulation J which is acommercially available PENLAC® NAIL LACQUER (ciclopirox) 8% TopicalSolution (Dermik Laboratories, Bridgewater, N.J.). An additionalformulation was Formulation K which is a commercially marketed LOCERYL®NAIL LACQUER (amorolfine) (Galderma Australia), currently marketed incountries other than the United States. Prior art formulations J and Kcontain film forming polymeric agents and form a lacquer uponapplication to the surface of a nail.

Example 11 Determination of Surface Tension of Formulations of Example10

The surface tensions of Formulations H to K of Example 10 weredetermined by the method described in Example 6. The surface tensionvalue for each of the formulations is shown below in Table 10.

TABLE 10 Formulation H I J K Surface Tension 72.5 24.6 22.7 23.7(dynes/cm)

Example 12 Determination of Spreadability of Formulations of Example 10

The spreadability of Formulations H to K of Example 10 was determined bythe method described in Example 9. Data is shown in Table 11.

TABLE 11 Formulations Minutes H I J K Single Slide 1 1.2 14.2 1.4 4.0Spreadability 2 1.2 14.2 1.4 4.0 Area (cm²) 4 1.2 14.2 1.4 4.0 6 1.214.2 1.4 4.0 10 1.2 14.2 1.4 4.0

Formulations H and I are controls that consist of water and twovehicles, respectively. Prior art formulations J and K contain filmforming polymeric compounds. As shown in Examples 11 and 12,Formulations H to K are not suitable for the present composition andmethod.

Example 13 Determination of Surface Tension and Spreadability ofFormulation of the Invention without Active Ingredients

Table 12 shows a formulations of the present invention, but lacking anactive pharmaceutical ingredient, that was made and tested for surfacetension as described in Example 6 and for spreadability as described inExample 9. Although this formulation lacks an API, it represents anexample of the formulation of the invention upon the inclusion of anAPI.

TABLE 12 Primary Formulation Material Function L (% w/w) Alcohol Vehicle63.04 Cyclomethicone Wetting Agent 13.67 Diisopropyl Adipate NonvolatileSolvent 12.62 C12-15 Alkyl Lactate Nonvolatile Solvent 10.52 Vitamin EAntioxidant 0.05 BHT Antioxidant 0.1 Tests Performed Surface Tension(dynes/cm) 21.8 Spreadability at 10 minutes (cm²) 33.2

Example 14 Formulations Including an APIs

The following examples in Table 13 represent formulations of theinvention that include representative APIs to illustrate the versatilityand utility of low surface tension formulations for improved efficacy inthe topical treatment of nail disease.

TABLE 13 Primary Formulation M Formulation N Formulation O FormulationFormulation Q Material Function (% w/w) (% w/w) (% w/w) P (% w/w) (%w/w) Ciclopirox Antifungal 8.0 — — — — Halobetasol Corticosteroid — — —0.05 — Propionate Urea Keratolytic — — 30.0 — — Erythromycin Antibiotic— 2.0 — — — KP-103 Antifungal — — — — 10.0 Alcohol Vehicle 61.4 67.5 —64.95 54.85 Purified Water Vehicle 5.0 5.0 53.0 — — Hexylene GlycolVehicle 25.0 25.0 — — — Propylene Vehicle — — 15.0 — — Glycol SodiumLauryl Wetting Agent 0.5 0.5 2.0 — — Sulfate Cyclomethicone WettingAgent — — — 13.0 13.0 Diisopropyl Nonvolatile — — — 12.0 12.0 AdipateSolvent C12-15 Alkyl Nonvolatile — — — 10.0 10.0 Lactate Solvent VitaminE Antioxidant — — — — 0.05 BHT Antioxidant 0.1 — — — 0.1

One general method for making the compositions in Table 13 is asfollows. For lipophilic APIs such as halobetasol propionate and KP-103,the API is first dissolved n alcohol with propeller mixing, followed bythe addition and dissolution of the antioxidants, if any. Next a wettingagent is added with continued mixing. Finally one or more non-volatilesolvents are added to the formulation.

For the lipophilic APIs erythromycin and ciclopirox, a wetting agent isdissolved in the water with propeller mixing. This mixture is added tohexylene glycol with mixing. Next the alcohol is added. The API alongwith the antioxidant, if any, is then added to the mixture and which ismixed until the API is dissolved using propeller mixing. For thehydrophilic API urea, the sodium lauryl sulfate is dissolved in waterwith propeller mixing. The API is added next with continued mixing untildissolved. Finally the propylene glycol is added and mixed. The laststep for all compositions is packaging in tightly-closedpharmaceutically acceptable containers.

Example 15 Clinical Efficacy in Onychomycosis

The composition of Example 14, formula Q, containing 10% KP-10, wasevaluated in a double-blind vehicle-controlled parallel-group clinicalstudy for the treatment of toenail onychomycosis. Efficacy was assessedby an investigator 40 weeks after the start of treatment based on adesignated great toenail with average disease involvement of 40% (range20 to 90%) at the beginning of the study. Patients made once dailyapplications of the test composition or the vehicle (same compositionwith active agent KP-103 replaced with alcohol) to the affected toenailsfor 36 weeks, with efficacy assessments being made at the follow-upvisit 4 weeks later. Complete cure was defined as clear nail (no diseaseinvolvement) plus negative mycology. Almost clear was defined asnegative mycology plus clear nail or growth of 3 mm or more of new clearnail. The frequency of clinical success calculated as complete cure andalmost clear is summarized in Table 14.

TABLE 14 Parameter KP-103, 10% Vehicle (no API) Number of Subjects 39 22Complete Cure - Number 10 2 Complete Cure - Percent 25.6 9.1 AlmostClear - Number 25 5 Almost Clear - Percent 64.1% 22.7%

Table 14 shows that the formulation of the invention provided anefficacy much higher than that obtained by presently available topicalformulations. The present formulation provided a success rate that isdramatically higher than that obtained by present topical and even somesystemic methods of treatment of onychomycosis. The present formulationprovided three and a half times more complete cures than reported forPenlac Nail Lacquer and from 0.66 to 1.8 times the complete curesreported for itraconazole and terbinafine, respectively, two orallyadministered antifungal drugs approved in the USA for treatment ofonychomycosis.

While preferred embodiments of the invention have been described indetail, it will be apparent to those skilled in the art that thedisclosed embodiments may be modified. It is intended that suchmodifications be encompassed in the following claims. Therefore, theforegoing description is to be considered to be exemplary rather thanlimiting, and the scope of the invention is that defined by thefollowing claims.

The invention claimed is:
 1. A pharmaceutical composition for thetopical treatment of a disorder of the nail or nail bed comprising a.ethanol, 50% to 70% (w/w), b. cyclomethicone, 10% to 15% (w/w), c.diisopropyl adipate, 8% to 15% (w/w), d. C12-15 alkyl lactate, 8% to 15%(w/w), e. antioxidant, 0.001% to 0.50% (w/w), and f.(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol,2% to 15% (w/w); wherein the composition is formulated as a solution;wherein the surface tension of the composition is 40 dynes/cm or less;and wherein the composition does not comprise a polymeric film formingcompound.
 2. The pharmaceutical composition of claim 1 comprising(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-olin an amount of about 10%.
 3. The pharmaceutical composition of claim 1,wherein the surface tension of the composition is 30 dynes/cm or less.4. The pharmaceutical composition of claim 1 comprising(2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidine-1-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-olin an amount of about 10%, and wherein the surface tension of thecomposition is 25 dynes/cm or less.